Spinal Cord Stimulation for Spinal Cord Injury

Abstract

Spinal cord injury is a medically complex and life-disrupting condition, associated with very high mortality rates (early death rates after admission range from 4 to 20%). In addition, it’s complicated subsequent severe disability due to the development of early or late complications. Today, in high-income countries, SCI can be viewed less as the end of a worthwhile or productive life and more as a personal and social challenge that can be successfully overcome. SCI can be divided into two types of injury on the basis of severity: complete and incomplete injury. Damage to the spinal cord may be traumatic (falls, road traffic injuries, occupational and sports injuries, violence) or non-traumatic (infectious disease, tumor, musculoskeletal disease, congenital problems such as spina bifid).

1. Introduction

Most demographic and epidemiologic data related to TSCI in the United States have been collected by the Model Spinal Cord Injury Care Systems and are published by the National Spinal Cord Injury Statistical Center [1]. The WHO has focused on this problem by publishing “International Perspectives on Spinal Cord Injury” in 2020 [2]. According to the aforementioned records, SCI is a relatively rare but life-altering and costly condition, with a mortality risk that varies widely by country income status and depends heavily on the availability of clinical care of high quality and rehabilitation services. It is unclear how many people in the world are currently living with SCI, but international incidence data suggest that every year between 250,000 and 500,000 people receive a spinal cord injured [2].

Traumatic spinal cord injury (TSCI) remains a costly problem for society; direct medical expenses accrued over the lifetime of one patient range from 500,000 to 2 million US dollars [3].

Up to 90% of SCI has been traumatic in origin, but data from the most recent studies indicate a slight trend in recent years toward an increase in the share of non-traumatic spinal cord injury [4]. It can be related to the increased life expectancy of the population. Age and gender also influence etiological causes (medical and surgical causes of SCI are most prevalent under the age of 1 year, road traffic crashes, sports, and violence remain the most common cause in the older group more common among men) [2].

There are far fewer studies on non-traumatic spinal cord injury incidence. It mainly represents the specific studies on spina bifida. Age and gender also influence etiological causes in this group too. As with the traumatic group, incidence rates are higher among males than females and more common in older age groups [5]. Studies suggest that the leading causes are neoplastic tumors and degenerative conditions of the spinal column, followed by vascular and autoimmune disorders, but congenital and genetic cases of spinal cord injury were not included in these studies [2, 6, 7, 8].

2. Clinical presentation

The neurological damage caused by both traumatic and non-traumatic SCI prevents sensory and motor information from traveling to and from the brain below the level of the injury. The impact of SCI on function will depend on the level and severity of the injury and the available health care. SCI-related morbidities, include senso-motor deficit, neuropathic pain, spasticity and bladder, and bowel and sexual dysfunction. Higher neurologic level and severity of the injury and older age at the time of SCI negatively impact survival. In general, the higher the lesion, the wider the range of impairment. Among SCI incidences since 2015, approximately 30% of injuries are complete, resulting in no function beyond the level of injury. About 60% of SCI cases are incomplete, where some levels of communication between the central and peripheral nervous system are maintained [9]. The severity of SCI is graded on the scale from A to E according to the American Spinal Injury Association (ASIA), with Grade A indicating complete spinal cord injuries and Grade E signifying fully-restored sensorimotor functions [10].

3. Pain syndrome

Most people with SCI experience chronic pain, which can have a significant impact on their quality of life, causes significant suffering and reduces social interactions. Pain may also exacerbate other comorbidities of SCI, as well as delay wound healing and recovery of motor function.

Although the key focus of SCI treatment is the recovery of motor function, improvements in the secondary outcomes, especially pain, are equally important to patients [11]. Turner et al. reported that 79% of 384 subjects with SCI experienced painful sensations; Rintala et al. found that 75% of 77 patients with SCI reported chronic pain [12, 13]. It has been estimated that 30–80% of SCI patients experience chronic pain that develops unilaterally or bilaterally after injury. Strikingly, nearly one-third of SCI patients suffer severe pain [14].

Neuropathic pain is one of the most disabling consequences of spinal cord injury and is observed in about 40–50% of patients with chronic SCI, has a mean onset of 1.2 years after injury [15, 16]. Chronic pain after spinal cord injury can be divided into three distinct categories:

1. Neuropathic pain—a result of damage to the spinal cord, usually characterized as burning, stabbing, aching, and/or electric-like stinging sensations.

   1. Central neuropathic pain—pain due to syringomyelia or posttraumatic myelopathy;

   2. Peripheral neuropathic pain—pain due to muscle spasticity or radiculopathy;

2. Nociceptive pain—the musculoskeletal pain as a result of overuse, e.g. shoulder pain from constantly pushing a manual wheelchair, muscle spasms, mechanical instability, or poor posture.

3. Nociplastic pain—these populations are at increased risk of depression, anxiety, pain, and poorer quality of life (QoL) [17].

The two or three types can also be combined in one patient.

The second classification considered neuropathic pain following spinal cord injury is categorized into pain at and pain below the level of the lesion. At-level pain may be caused by the spinal cord or nerve roots lesions, e.g., it may have peripheral or central mechanisms while below-level pain is considered as central pain caused by the spinal cord injury [18].

3.1 Physiology of neurogenic pain after SCI

Neurogenic pain refers to pain generated by a nerve. After trauma to any nerve fibers, damaged nerves may start to send incorrect signals toward the brain. Most commonly these signals may cause a shooting or burning sensation in the related area. Other times this may cause increased sensitivity to touch. The end result is an unpleasant experience in the affected area.

3.2 Treatment

Both pharmacological and non-pharmacological interventions have been tried for different manifestations of SCI pain. Unfortunately, SCI pain is often refractory to current pharmacological therapies, including opioids, antidepressants, and anticonvulsants [14, 19].

In addition, long-term drug treatment often leads to severe dose-limiting side effects, such as addiction and abuse [20, 21, 22, 23].

4. Neuromodulation

4.1 Stimulation methods

Neurostimulation can be divided into invasive and non-invasive. Non-invasive methods include transcutaneous electrical stimulation, transcranial magnetic/direct current/alternating current stimulation. More invasive approaches involve the placement of electrodes closer to target areas of stimulation, such as the epidural space in the spinal column or directly into the brain.

Oftentimes, especially in the field of pain control, patients are given a certain degree of freedom to self-manage the stimulation intensity and patterns to achieve their own desired outcomes. Many systems have a simple and intuitive remote, which allows patients to achieve this, allowing for a certain degree of autonomy in their treatment.

Functional neuromodulation therapies may become important alternative strategies to alleviate pain symptoms when pharmacotherapies are ineffective or become intolerable [14, 24].

Neuromodulation therapies are targeted, they can avoid side effects associated with more systemic or irreversible treatments of nervous system disorders. And being easily reversible, they can provide an important degree of therapeutic control for patients and physicians. Functional neurostimulation therapies improve outcomes of SCI, such as alleviating neuropathic pain, regaining motor function, alleviating spasticity, and improving bowel and bladder control [24].

Neuromodulation strategies may be noninvasive or invasive, the latter requiring a surgical procedure. The most common neuromodulation therapy is spinal cord stimulation to treat chronic neuropathic pain.

Spinal cord stimulation (SCS) has been used for over 50 years to manage pathologic pain conditions. The best result for persistent spinal pain syndrome, diabetic neuropathy, and critical limb ischemia (strongly recommended). Yet, its usefulness and mechanisms of action in SCI pain are still unclear [25, 26, 27, 28].

Conventional SCS has been used for several decades in SCI patients to help them regain motor control below the level of the lesion, improve bone and muscle health, and attenuate spasticity [27].

Because of the small number of studies, the use of spinal cord stimulation for pain after spinal cord injury in patients does not have a level of evidence, therefore, clinical use is still limited and it is necessary to consider on a case-by-case basis. Spinal cord injury patients with central neuropathic pain may respond to SCS if there is segmental pain at the level of injury as opposed to diffuse pain below the injury [25]. Also, most research induces better pain relief in patients with an incomplete cord lesion than in those with complete cord transection [29, 30]. Also, the use of SCS has been shown to reduce opioid use and improve function in patients with other pain conditions, a very important consideration in light of the current epidemic of opioid addiction and abuse [31].

Nowadays the field of neuromodulation is progressively evolving showing significant advancement in therapeutic efficacy. There is a growing number of new modes or targets of neurostimulation, continuous improvement in existing approaches, and steady reduction in complications [32].

Despite long-standing application the long-term outcomes of SCS for SCI pain from the limited number of studies are not promising. Unfortunately, a large number of studies have been conducted during the period from the 70s to 90s. The last two most relevant studies are presented in Table 1.

Study	SCI injury; level	SCI injury severity	SCS level	Outcomes and comments
Levine et al. [33]	Cervical	Not mentioned	Cervical	6/9 mean VAS pain score dropped from 7.8 (±1.2) to 2.7 (±0.6) at 12-month follow-up (VAS decreased C 50%)
Reck and Landmann [34]	T5	Complete severe pain in both legs and feet	T11–L1 (below lesion)	1 responder/1 at 3 months

Table 1.

Previous studies looking specifically at efficacy of SCS in SCI with outcomes.

Only 50–60% of patients respond to initial trial stimulation (defined as 50% pain reduction). Further, only a portion of these selected patients’ experience pain relief by SCS [35, 36].

Burst SCS (bursts of 5 pulses with an internal frequency 500 Hz) applied at 40 Hz was developed as an alternative to conventional SCS. Burst SCS can attenuate pain without eliciting paresthesia and may induce better neuropathic pain inhibition than conventional SCS. Nevertheless, clinical evidence to support the use of burst SCS for managing chronic intractable pain is still insufficient [37]. High-frequency, paresthesia-free SCS (10,000 Hz) has emerged as another paradigm that has further improved the clinical outcomes for neuropathic pain [38].

5. Further opportunities SCS for SCI

Improving motor, sexual, bowel, and bladder function has been noted as a priority related to overall quality of life (QOL) for persons with SCI. SCI can result in significant multisystem effects.

5.1 Spasticity

The multiple case reports, case series, pilot studies, and a few prospective publications suggest that SCS is able to reduce spasticity arising from over 25 different neurodegenerative and traumatic etiologies, including spinal cord injury. Most early studies that explored spasticity management using SCS were carried out in the 1970s and 1980s too [39].

5.2 Urinary complications

SCI produces bladder dysfunction, often referred to as the neurogenic bladder. Other complications can result from this, including infections, vesicoureteral reflux, renal failure, and renal calculi. SCS can be used to modulate autonomic circuits involved in the lower urinary tract and bowel control after SCI. SCS activates autonomic and motor spinal cord circuits that affect the lower urinary tract, external, anal sphincter/pelvic floor, and bowel function in individuals after chronic motor-complete SCI. There has been an interest in bladder neuromodulation as early as 1879 when Saxtorph directly stimulated the bladders of patients in retention with a metal transurethral catheter [40]. Since then, a number of techniques have been developed to perform neuromodulation of the bladder and urinary sphincter, particularly for persons with neurogenic bladders. Herrity et al. tested different electrode configurations and stimulation parameters (frequency and pulse width) to optimize voiding efficiency following SCI [41]. Despite these emerging findings, further research is necessary to reveal how autonomic connections are altered after injury and to fully identify the underlying mechanistic pathways responsible for observed functional autonomic improvements with spinal cord stimulation [42]. SCS has the potential to play a very important role in bladder management following SCI since it can be designed with a phasic on and off switch network much like that of a normally functioning bladder and sphincter.

5.3 Motor function

Regaining motor control is extremely important to those who sustain a SCI. Even the ability to regain a small amount of voluntary motor control might improve functional capability and improve a person’s QOL. While the study is relatively new in this area, SCS have been shown to improve lower and upper-extremity motor control after SCI. Harkema and Edgerton’s group was the first to report preliminary data for SCS of the caudal segments (L5-S1) in a person with motor complete and sensory incomplete SCI (T6, ASIA Impairment Scale (AIS) B), 3 years post-injury with good efficiency. In 2018, three different laboratories reported independent overground walking and independent treadmill stepping with spES of the lumbosacral spinal cord for individuals with chronic motor complete injuries and limited ambulation in motor incomplete individuals [43, 44, 45].

5.4 Cardiovascular impairment

In addition to motor and bladder impairment, SCI impacts cardiovascular control in people with injuries at and above the T6 level. Numerous problems are caused by this including continuous blood pressure fluctuations in the form of hypotension and orthostatic hypotension due to autonomic dysreflexia. SCS have been shown to improve autonomic cardiovascular function after SCI, specifically relating to BP control. West et al. applied stimulation at T11 to L1 using a 16-electrode array in an attempt to increase BP in a person with C5 AIS B tetraplegia. This resulted in a rise in BP, preventing a decrease in middle cerebral artery blood flow during an orthostatic challenge. This resolved orthostatic symptoms including light-headedness, dizziness, and poor concentration that were reported by the patient without stimulation [46]. Harkema et al. reported on four individuals with chronic C4 motor complete SCI (3 AIS A and 1 AIS B). This study was able to prove a significant and reproducible increase in mean arterial pressure using a 16-electrode array implanted on the dura at L1-S1. The blood pressure was able to be maintained between 110 and 120 mmHg. These results were obtained without making any substantial changes to heart rate [47].

6. Conclusion

Neuropathic pain due to spinal cord injury is particularly challenging to treat. SCS lacks systemic side effects, and compared to neuroablation, SCS is adjustable and reversible. These features make SCS promising in the treatment of SCI pain. SCS has been shown to reduce medical treatment, especially opioids. Neuromodulation for SCI is a need for large multicenter placebo-controlled trials in neuropathic pain. Some issues remain important as to why SCS is effective in some patients but may not be effective in others. Currently, a study is underway of SCS for SCI (Spinal cord stimulation Phase I NCT02592668). This will be a retrospective study, though the final number of patients to be included in the study has not yet been finalized.